Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents

[Display omitted] Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal str...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-04, Vol.29 (8), p.1023-1029
Main Authors: Francis, Stuart, Croft, Daniel, Schüttelkopf, Alexander W., Parry, Charles, Pugliese, Angelo, Cameron, Ken, Claydon, Sophie, Drysdale, Martin, Gardner, Claire, Gohlke, Andrea, Goodwin, Gillian, Gray, Christopher H., Konczal, Jennifer, McDonald, Laura, Mezna, Mokdad, Pannifer, Andrew, Paul, Nikki R., Machesky, Laura, McKinnon, Heather, Bower, Justin
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - metabolism
Binding Sites
Cancer
Carrier Proteins - antagonists & inhibitors
Carrier Proteins - metabolism
Crystallography, X-Ray
Drug Design
Drug discovery
Fragments
Humans
Inhibitory Concentration 50
Medicinal chemistry
Microfilament Proteins - antagonists & inhibitors
Microfilament Proteins - metabolism
Molecular Docking Simulation
Protein Structure, Tertiary
Pyrazoles - chemistry
Pyrazoles - metabolism
Pyridines - chemistry
Pyridines - metabolism
Quinolones - chemistry
Quinolones - metabolism
Structure-Activity Relationship
Virtual screening
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Summary:[Display omitted] Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2019.01.035